14.2 - Metabolic + Endocrine Control During Special Circumstances Flashcards
What are the main fuel sources normally available in the blood
glucose
- Preferred fuel source
- Little free glucose available, most stored as glycogen
- Some cells have an absolute requirement for glucose (different card)
fatty acids
- Can be used as fuel by most cells
- Stored as triacylglycerol (fat) in adipose tissue
- 10-15kg fat in 70kg man
- Roughly 2 months energy store
- Generate energy (ATP) using β oxidation
What cells have an absolute requirement for glucose
- Some lymphocytes
- Kidney medulla
- Cells of cornea
- Red blood cells (have no mitochondria)
- Brain (can gradually adjust to using ketone bodies)
- CNS
These cells rely on glycolysis and glucose is their only energy source
What are the fuel sources available under special conditions
amino acids
- Breakdown of skeletal muscle
- Converted to glucose or ketone bodies
- Roughly 2 weeks supply of energy
ketone bodies
- Mainly from fatty acids
- Used when glucose is critically short
- Glucose sparing effect (where glucose is saved for the cells that have obligate requirement eg CNS)
- Brain can gradually adjust to metabolising this instead of glucose
lactate
- Product of anaerobic metabolism in muscle
- When oxygen runs out, muscle produces lactate from pyruvate
- Lactate can be recycled in liver by being converted back to glucose (Cori cycle)
- Or can be used as a fuel source for TCA cycle in other tissues eg in heart
What are the main energy stores in the body
glycogen
- Readily available source of glucose
- Made and stored in liver + muscle
- Made when excess glucose in blood
fat
- Made from glucose + dietary fats when in excess
- Stored as triacylglycerol in adipose tissue
- Source of fatty acid + glycerol
muscle protein
- Used in emergency
- Amino acids can be glucogenic and/or ketogenic
- Store is ‘filled’ by normal growth and repair processes
note: Ketogenic amino acids form acetoacetate or acetyl CoA. Glucogenic amino acids form pyruvate, α-ketoglutarate, succinyl CoA, fumarate, or oxaloacetate
Key features of metabolic control
after feeding, glucose and fat are available from gut
- Immediate metabolism supported by glucose
- Increase rate of growth and repair processes
- Make glycogen rapidly + increase fat stores
after eating, glucose and fats no longer being absorbed
- Maintain blood glucose by using glycogen stores
- Support other metabolic activity with fatty acids from stores
- Preserve blood glucose for brain
after glycogen stores depleted
- Gluconeogenesis from AAs, glycerol and lactate
- Continue to support other metabolism with fatty acids
prolonged starvation
- Fatty acid metabolism produces ketone bodies
- Brain adjusts to be able to metabolise ketone bodies
- This reduces brain’s need for glucose
Catabolic + anabolic hormones for metabolic control
anabolic hormones
- Promote fuel storage
- Eg insulin – a lack of this → catabolic state
- Growth hormone (inc protein synthesis + gluconeogenesis)
catabolic hormones
- Promote release + use of energy stores
- Eg thyroid hormones, adrenaline + cortisol (promote increase in BMR)
- Eg glucagon
- Eg growth hormone (increases lipolysis + glycogenolysis)
Effects of insulin (basic)
stops
- Gluconeogenesis
- Lipolysis
- Proteolysis
- Ketogenesis
- Glycogenolysis
go
- Glycolysis
- Glycogen synthesis
- Protein synthesis
- Promoting translocation of GLUT4 which allows tissues to take up glucose from meal to utilise in glycolysis or store (by muscle and adipose)
Effects of feeding
- Increase in blood glucose stimulates β cells in pancreas to release insulin
- Increases glucose uptake by GLUT4 and utilisation by muscle or adipose
- Promotes storage of glucose as glycogen in liver and muscle
- Promotes amino acid uptake + protein synthesis in liver and muscle
- Promotes lipogenesis and storage of fatty acids as triacylglycerols in adipose tissue
Effects of fasting
- Blood glucose falls
- Insulin secretion depressed
- Reduces uptake of glucose by adipose and muscle
- Low blood glucose stimulates glucagon from α cells
- Glucagon stimulates
☞ glycogenolysis in liver to maintain blood glucose for glucose dependent tissues
☞ lipolysis in adipose tissue to provide fatty acids for use by tissues
☞ gluconeogenesis to maintain supplies of glucose for dependent tissues
Energy starvation
- Reduction of blood glucose → stimulates release of cortisol (from adrenal cortex) and glucagon (α pancreas)
- Stimulate gluconeogenesis, proteolysis + lipolysis for energy
- Insulin effects reduced, preventing cells from using glucose
- Fatty acids are preferentially metabolised
- Glycerol from fat is substrate for gluconeogenesis, reducing need for proteolysis
- Glucose sparing effect: Liver produces ketone bodies → brain starts to use these
- Kidneys begin to contribute to gluconeogenesis
- Once fat stores depleted, protein sources used as fuel
- Death usually related to loss of muscle mass (eg diaphragm and therefore breathing compromised)
What is a mother’s net weight gain by end of pregnancy
- roughly 8kg
- This consists of foetus, placenta, amniotic fluid and maternal fuel stores
- Require most energy during final trimester as this is when most foetal growth occurs
Two main phases of metabolic adaptation during pregnancy
anabolic phase
- Early pregnancy
- Preparatory increase in maternal nutrient stores (particularly adipose)
- This is because need energy stores for rapid growth (third trimester) and preparation for lactation
- Small increase in insulin sensitivity so that fat can take up more glucose
catabolic phase
- Later pregnancy
- Maternal metabolism adapts to meet an increasing demand by fetal-placental unit
- Decreased insulin sensitivity (increased insulin resistance)
- This promotes availability of glucose for foetus
- Increase in insulin resistance results in an increase in maternal glucose + fatty acid concentration so that there is greater availability for foetus
How do substances get across placenta
- Most by simple diffusion down concentration gradient
- Some active transport eg amino acid transporters
glucose
☞ prinicipal fuel for foetus
☞ transfer across placenta facilitated by GLUT1 transporter
☞ GLUT1 is concentration-dependent (not insulin dependent)
What is fetoplacental unit
- Foetus controls maternal metabolism to ensure its own survival
- Aka ‘aggressive parasite’
- New endocrine entity (fetoplacental unit) = placenta, fetal adrenal glands and fetal liver
- Wide range of hormones/proteins produced by placenta that can control the maternal hypothalamic pituitary axis
- Eg CRH, GnRH, TRH, GHRH (hypothalamic like releasing hormones) and ACTH, hCG, cCT, hPL (pituitary like hormones)
- Some steroid hormones also produced eg oestriol + progesterone
Maternal metabolic changes during first half of pregnancy
increased insulin : anti-insulin ratio
- Related to preparatory increase in maternal nutrient stores
- This is mainly increase in adipose tissues
- In preparation for rapid growth of foetus, lactation and birth
- increasing levels of insulin (therefore increased insulin : anti-insulin ratio)
- anti-insulin hormones = cortisol + adrenaline etc
- this promotes an anabolic state in mother that results in increased nutrient storage
maternal metabolic changes during second half of pregnancy
decreased insulin : anti-insulin ratio
- maternal metabolism adapts to meet increasing demands of foetus
- concentration of nutrients in the maternal circulation kept relatively high due to…
☞ glucose sparing: reduce maternal use of glucose by switching tissues to use fatty acid
☞ delay maternal disposal of nutrients after meals → better transfer of glucose to foetus
☞ release fatty acids from stores
- maternal insulin levels continue to increase
- however, production of anti-insulin hormones (by fetoplacental unit) increases at even faster rate
- therefore insulin : anti-insulin rate falls
why can pregnancy result in hyperglycaemia
- placenta secretes several hormones that exert an anti-insulin effect on maternal metabolism
- can result in transient hyperglycaemia due to increased insulin resistance
- insulin levels are still increased during pregnancy, but there are greater amounts of anti-insulin hormones
why can hypoglycaemia occur in pregnancy (between meals and at night)
foetus is continually drawing glucose from mother
insulin secretion in pregnancy
- increased appetite during pregnancy
- means more glucose ingested
- oestrogen + progesterone increase sensitivity of maternal β pancreas cells to glucose… this is done by β cell hypertrophy + hyperplasia
- this increases insulin synthesis and secretion
- if β cells don’t respond normally, blood glucose can become very elevated → can develop gestational diabetes
- more about this on next cards
what is gestational diabetes and the 3 known underlying causes
disease in which pancreatic β cells do not provide sufficient insulin to meet increased requirement in late pregnancy
☞ affects 3-10% of pregnancies
- β cell dysfunction in setting of obesity + insulin resistance (evolving T2 DM, predisposed to T2). Most common.
- Autoantibodies similar to those characteristically in T1 DM. Rarer.
- Genetic susceptibility similar to maturity onset diabetes. Rare.
Complications of gestational diabetes
- Increased incidence of miscarriage
- More likely to have congential malformation
- Fetal macrosomia (big baby) → childbirth problems related to baby size
- Extra adipose tissue around shoulders and chest → shoulder dystocia (shoulders get stuck)
- Hypertension: preeclampsia + gestational hypertension risk
The risk of complications is reduced if diagnosed + managed
How does starting point of insulin resistance before pregnancy affect risk of developing gestational diabetes?
- Naturally, insulin resistance increases with age
- This is due to having more fat and less lean body mass
- If start with low insulin resistance before pregnancy, pregnancy will be unlikely to cause diabetes threshold to be reached
- If start with higher insulin resistance (high risk woman) before pregnancy, pregnancy will cause increased insulin resistance
- This could reach diabetes threshold, causing gestational diabetes
- Will revert back to pre-diabetic state after preganancy
- However, the presence of gestational diabetes suggests that woman is more likely to develop T2 DM later in life
Risk factors for gestational diabetes
- Maternal age over 25 (more likely to reach diabetic threshold of insulin resistance during pregnancy, as insulin resistance already increases with age)
- BMI of over 25 kg/m2
- More common in Asian, black and hispanic ethnic groups
- Personal or family history of diabetes
- Family history of macrosomia (big baby)
What is the management of gestational diabetes
- Initial dietary modification, inc calorie reduction in obesity
- Insulin injection if persistent hyperglycaemia present
- Regular monitoring to reduce risk of complications
- This includes regular ultrasound scans to assess fetal growth
Metabolic response to exercise
- Very rapid switch from resting to exercise state
- Need to provide energy to meet increasing deman
- Involves adaptations in resp, cardio, msk + temperature regulation systems
- Minimal disturbances to metabolism homeostatis by keeping energy mobilisation equal to rate of utilisation
- Need to ensure enough glucose for dependent tissues
- Need to ensure products are removed as quickly as possible eg acid
- Response depends on type of exercise (muscles used), intensity, duration of exercise, physical state and nutrition of individual
Energy requirements of exercise
- ATP → ADP + Pi + energy
- Need this for power stroke for sliding filament theory to facilitiate muscle contraction
- Also need for other cellular processes eg maintaining ionic gradients across the cell membrane
- ATP stores in muscle are very limited
- ATP must be rapidly resynthesised at a rate that meets metabolic cell demands
- Cell will employ different metabolic strategies to match resynthesis with rate of hydrolysis
- Can use creatine phosphate stores to rapidly replenish ATP (from ADP) to provide immediate energy. However this is very short-lived but provides enough time fo glycolysis to kick in
- Beyond initial burst of energy, further ATP must be supplied by glycolysis + oxidative phosphorylation (so need to draw on energy stores)
How is muscle glycogen used during exercise
☞ Anaerobic breakdown of glycogen (producing lactate) can sustain some intense exercise
☞ If exercise is low intensity enough, O2 can be supplied for complete oxidation of glucose + glycogen stores (from muscle and liver)
- glycogenolysis by muscle glycogen phosphorylase. This is increased by adrenaline + AMP. Produces Glucose 6 Phosphate which is used in glycolysis
- Glycolysis is regulated by phosphofructokinase, which is stimulated by high AMP and inhibited by high ATP.
- Pyruvate is produced, and can enter TCA cycle in aerobic conditions, and lactate is end product under anaerobic conditions
- Lactate can be recycled by Cori cycle, taken to liver and converted to glucose again, which is fed back to muscle.
What is the Cori Cycle
- The liver recycles the lactate produced by anaerobic metabolism
- Lactate produced anaerobically by muscle is transported to liver by bloodstream
- Liver converts 2 lactate into glucose
- Glucose is transported to muscle where it can be used in respiration
What is the prinicipal organ for regulating blood glucose
- The liver
- Exercise results in an increase in hepatic blood glucose production through glycogenolysis and gluconeogenesis
- Liver recycles lactate produced from anaerobic metabolism (Cori Cycle, card above)
How does muscle take up blood glucose
- Predominantly via GLUT4 (insulin promotes translocation to plasma membrane)
- Also via GLUT1 (constituitevly active, meaning it’s insulin independent)
- Exercising muscle also has insulin independent process of glucose uptake…
☞ increase in AMP → stimulates AMPK → signalling cascade → promotes GLUT4 translocation → more glucose uptake into cells - Rate of glucose production from liver is insufficient to meet full demands of exercising muscle
Fatty acids as fuel
- Triacylglycerol is mainly stored in adipose, but also some in muscle itself
- Can only be used in aerobic conditions
- Slow release from adipose tissue
- Not easily transported in blood – limited carrying capacity
- Capacity limited by uptake across mitochondrial membrane (carnitine shuttle)
- Low rate of ATP production
- High capacity for sustained production
Short, high intensity exercise
- Eg 100m sprint
- Cannot deliver enough O2 to muscles in time
- Once high energy phosphate stores used, must revert to anaerobic respiration
- This creates ATP inefficiently due to incomplete metabolism of glucose (this is going to lactate, not TCA cycle)
- The lactate produced → build up of H+
- This causes fatigue + cramps
- Need muscle store of glycogen: has glucose sparing effect so that glucose is saved for glucose-dependent tissues
Middle distance exercise, medium intensity
- Eg 1500m
- Can deliver some extra O2 but significant part still anaerobic
- Aerobic can use fatty acid metabolism as well as glucose
- Initial start uses creatine phosphate and anaerobic glycogen metabolism
- Long middle phase relies on O2 delivery to tissues → ATP produced aerobically
- Finishing sprint relies again on anaerobic metabolism of glycogen…produces lactate
Long distance + long duration exercise
- Eg marathon
- Low intensity but long
- Mainly aerobic respiration
- Use of muscle + liver glycogen, and fatty acid metabolism
- Muscle glycogen is depleted quickly
- Liver glycogen is used and then depletes
- Fatty acid utilisation
Hormonal control of the metabolic response to prolonged exercise
Eg in marathon
* insulin falls slowly due to adrenaline production. Adrenaline inhibits insulin
* glucagon rises:
☞ activates glycogen phosphorylase (stimulating glycogenolysis)
☞ activates PEPCK + fructose 1,6 bisphosphatase (stimulating gluconeogenesis)
☞ activates hormone sensitive lipase (stimulating lipolysis – release of fatty acids)
* adrenaline increases rapidly, stimulating glycogenolysis + lipolysis
* growth hormone increases rapidly to stimulate gluconeogenesis + lipolysis
* cortisol rises slowly, increasing lipolysis + gluconeogenesis
Benefits of exercise
- Body composition: decrease adipose, increase muscle
- Glucose tolerance improves
- Increased insulin sensitivity
- Decrease in VLDL + LDL, increase HDL
- Decrease in blood pressure
- Good psychological effects
- Reverses progression of metabolic disease
- Can improve T2 DM dramatically
